The pathogenesis of common cardiovascular diseases, including atherosclerosis and hypertension, involves diverse and complex pathways. Significant advances in our understanding of the underlying pathobiologies at a molecular and cellular level are increasingly leading to the development of new therapeutic strategies targeted at primary etiologies rather than secondary manifestations of vascular disease. Thus, it is essential for both inquisitive scientists and clinicians who are taking care of patients with cardiovascular disease to understand the normal physiology, signaling pathways, and function of the different cell types that constitute the layers of the vascular wall, in addition to the complex interactions between the vasculature, the heart and the entire human organism (Fig. 7–1). This chapter will provide relevant basic knowledge about the underlying physiology and function of each component of the vasculature and how disease conditions alter this carefully regulated system.
The integrative pathophysiology of atherosclerosis, ischemic heart disease, and the systemic inflammatory response. Atherosclerosis develops over many years (1) and can lead to myocardial infarction (2), while the stress of acute myocardial infarction (2) also produces an “echo” in atherosclerotic plaques (1). Acute myocardial infarction causes pain and anxiety that triggers sympathetic outflow from the central nervous system (3). β3 adrenergic stimulation mobilizes leukocyte progenitors from their bone marrow niche. These progenitor cells can migrate to the spleen, where they can multiply in response to hematopoietic growth factors. The proinflammatory monocytes then leave the spleen and enter the atherosclerotic plaque (1), where they promote inflammation that can render a plaque more likely to provoke thrombosis and hence acute myocardial infarction (2). IL, interleukin. Reproduced with permission from Libby P, Nahrendorf M, Swirski FK: Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded “Cardiovascular Continuum.” J Am Coll Cardiol. 2016 Mar 8;67(9):1091-1103. 192
Early Vessel Formation—Vasculogenesis
Vasculogenesis is the earliest form of vessel generation to occur; in fact, it is one of the earliest biologic programs in the developing embryo. Vasculogenesis has been recognized and studied for at least a century. 1 It is initiated soon after gastrulation (when the single-layered blastula is reorganized to form the ectoderm, mesoderm, and endoderm) by the aggregation of mesodermal progenitor cells into clusters referred to as blood islands, which are the earliest vascular structures. These clusters then undergo partial lineage commitment, with the outer cells becoming endothelial precursor cells (referred to as angioblasts) and the central cells becoming hematopoietic progenitor cells. Blood islands soon coalesce and fuse, and a central lumen emerges. These primitive vessels undergo progressive remodeling and maturation, and eventually a primitive vasculature emerges (Fig. 7–2).
Mechanisms of vessel formation. Vasculogenesis (top) has been extensively described during development and involves the coalescence of primitive cells to form vasculogenic networks. Angiogenesis ...